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Molecular and gene expression-based predictors of response to preoperative chemotherapy

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Many single-gene molecular markers have been evaluated as predictors of response to specific regimens. However, no reliable and routinely used molecular chemotherapy response predictors exist today. Molecular markers of proliferative activity remain nonspecific predictors of chemotherapy sensitivity in general. Multidrug-resistance transport proteins, p53 gene mutations, and defects in apoptotic pathways remain highly controversial as predictors of response or resistance to particular drugs. To date, the strongest (although still indirect) evidence supporting a molecular predictor of response to a particular regimen comes from a retrospective subset analysis of a variety of studies that showed a link between topoisomerase II amplification and increased sensitivity to anthracyclines. However, the best methodology for determining amplification of topoisomerase II and the appropriate cut-off value to distinguish between individuals with and without amplification have not been established.

Several small studies provided 'proof-of-principle' that the gene expression profile of cancers that are highly sensitive to chemotherapy is different from that of tumors resistant to treatment. Table 1 presents a summary of the current literature. The most exciting possibility implicit to gene expression profiling-based diagnostic tests is that multiple predictors could be applied to a single data set. It is currently technically feasible to perform gene expression profiling on a single biopsy and assess prognosis using a 76-gene, or 70-gene signature, determine the ER and HER-2 status by measuring receptor mRNA levels, predict endocrine sensitivity among the ER-positive patients and estimate the probability of response chemotherapy.

Table 1 Table 1


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    Ayers M, Symmans WF, Stec J, et al: Gene expression profiles predict complete pathologic response to neoadjuvant paclitaxel and fluorouracil, doxorubicin, and cyclophosphamide chemotherapy in breast cancer. J Clin Oncol. 2004, 22: 2284-2293. 10.1200/JCO.2004.05.166.

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    Iwao-Koizumi K, Matoba R, Ueno N, et al: Prediction of docetaxel response in human breast cancer by gene expression profiling. J Clin Oncol. 2005, 23: 422-431. 10.1200/JCO.2005.09.078.

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    Hannemann J, Oosterkamp HM, Bosch CA, et al: Changes in gene expression associated with response to neoadjuvant chemotherapy in breast cancer. J Clin Oncol. 2005, 23: 3331-3342. 10.1200/JCO.2005.09.077.

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    Gianni L, Zambetti M, Clark K, et al: Gene expression profiles in paraffin-embedded core biopsy tissue predict response to chemotherapy in women with locally advanced breast cancer. J Clin Oncol. 2005, 23: 7265-7277. 10.1200/JCO.2005.02.0818.

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    Folgueira MA, Carraro DM, Brentani H, et al: Gene expression profile associated with response to doxorubicin-based therapy in breast cancer. Clin Cancer Res. 2005, 11: 7434-7443. 10.1158/1078-0432.CCR-04-0548.

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    Dressman HK, Hans C, Bild A, Olson JA, et al: Gene expression profiles of multiple breast cancer phenotypes and response to neoadjuvant chemotherapy. Clin Cancer Res. 2006, 12 (3 Pt 1): 819-826. 10.1158/1078-0432.CCR-05-1447.

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    Thuerigen O, Schneeweiss A, Toedt G, et al: Gene expression signature predicting pathologic complete response with gemcitabine, epirubicin, and docetaxel in primary breast cancer. J Clin Oncol. 2006, 24: 1839-1845. 10.1200/JCO.2005.04.7019.

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    Park S, Shimizu C, Shimoyama T, et al: Gene expression profiling of ATP-binding cassette (ABC) transporters as a predictor of the pathologic response to neoadjuvant chemotherapy in breast cancer patients. Breast Cancer Res Treat. 2006, 99: 9-17. 10.1007/s10549-006-9175-2.

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    Cleator S, Tsimelzon A, Ashworth A, et al: Gene expression patterns for doxorubicin (Adriamycin) and cyclophosphamide (cytoxan) (AC) response and resistance. Breast Cancer Res Treat. 2006, 95: 229-233. 10.1007/s10549-005-9009-7.

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    Hess KR, Anderson K, Symmans WF, et al: Pharmacogenomic predictor of sensitivity to preoperative chemotherapy with paclitaxel and fluorouracil, doxorubicin, and cyclophosphamide in breast cancer. J Clin Oncol. 2006, 24: 4236-4244. 10.1200/JCO.2006.05.6861.

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    Mina L, Soule SE, Badve S, et al: Predicting response to primary chemotherapy: gene expression profiling of paraffin-embedded core biopsy tissue. Breast Cancer Res Treat. 2006, 103: 197-208. 10.1007/s10549-006-9366-x.

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  • Breast Cancer
  • Paclitaxel
  • Docetaxel
  • Gemcitabine
  • Epirubicin